CN107118157A - The design and synthesis of diphenyl urea analog derivative antitumoral compounds of one class containing pyrazol framework - Google Patents
The design and synthesis of diphenyl urea analog derivative antitumoral compounds of one class containing pyrazol framework Download PDFInfo
- Publication number
- CN107118157A CN107118157A CN201710511604.6A CN201710511604A CN107118157A CN 107118157 A CN107118157 A CN 107118157A CN 201710511604 A CN201710511604 A CN 201710511604A CN 107118157 A CN107118157 A CN 107118157A
- Authority
- CN
- China
- Prior art keywords
- arh
- compound
- structural formula
- reactant mixture
- reaction
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 title claims abstract description 14
- GWEHVDNNLFDJLR-UHFFFAOYSA-N 1,3-diphenylurea Chemical class C=1C=CC=CC=1NC(=O)NC1=CC=CC=C1 GWEHVDNNLFDJLR-UHFFFAOYSA-N 0.000 title claims abstract description 9
- 150000001875 compounds Chemical class 0.000 title claims description 42
- 238000013461 design Methods 0.000 title description 4
- 230000000259 anti-tumor effect Effects 0.000 title description 2
- 230000015572 biosynthetic process Effects 0.000 title description 2
- 238000003786 synthesis reaction Methods 0.000 title description 2
- 238000002360 preparation method Methods 0.000 claims abstract description 50
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims abstract description 9
- 239000007787 solid Substances 0.000 claims description 43
- 238000006243 chemical reaction Methods 0.000 claims description 40
- 239000000203 mixture Substances 0.000 claims description 40
- 239000000376 reactant Substances 0.000 claims description 37
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 36
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 25
- 238000003756 stirring Methods 0.000 claims description 20
- 230000004044 response Effects 0.000 claims description 16
- 238000001914 filtration Methods 0.000 claims description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 14
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 12
- 238000001035 drying Methods 0.000 claims description 12
- 239000012074 organic phase Substances 0.000 claims description 12
- -1 diphenyl ureas Chemical class 0.000 claims description 9
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 8
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 claims description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 8
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 8
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 8
- 230000006837 decompression Effects 0.000 claims description 8
- 238000001704 evaporation Methods 0.000 claims description 8
- 230000008020 evaporation Effects 0.000 claims description 8
- 238000010438 heat treatment Methods 0.000 claims description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 8
- 238000005406 washing Methods 0.000 claims description 7
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 6
- 229920006395 saturated elastomer Polymers 0.000 claims description 6
- 235000002639 sodium chloride Nutrition 0.000 claims description 6
- 239000011780 sodium chloride Substances 0.000 claims description 6
- 239000007788 liquid Substances 0.000 claims description 5
- 238000010898 silica gel chromatography Methods 0.000 claims description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 5
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 claims description 4
- YEDUAINPPJYDJZ-UHFFFAOYSA-N 2-hydroxybenzothiazole Chemical compound C1=CC=C2SC(O)=NC2=C1 YEDUAINPPJYDJZ-UHFFFAOYSA-N 0.000 claims description 4
- 229960000549 4-dimethylaminophenol Drugs 0.000 claims description 4
- 239000005725 8-Hydroxyquinoline Substances 0.000 claims description 4
- 229910021595 Copper(I) iodide Inorganic materials 0.000 claims description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 4
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 4
- 229910052786 argon Inorganic materials 0.000 claims description 4
- 239000003054 catalyst Substances 0.000 claims description 4
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 claims description 4
- 239000012043 crude product Substances 0.000 claims description 4
- 239000007789 gas Substances 0.000 claims description 4
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 claims description 4
- 238000005984 hydrogenation reaction Methods 0.000 claims description 4
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 claims description 4
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 4
- 229910017604 nitric acid Inorganic materials 0.000 claims description 4
- 229960003540 oxyquinoline Drugs 0.000 claims description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 4
- 239000002244 precipitate Substances 0.000 claims description 4
- 238000001556 precipitation Methods 0.000 claims description 4
- 150000003217 pyrazoles Chemical class 0.000 claims description 4
- MCJGNVYPOGVAJF-UHFFFAOYSA-N quinolin-8-ol Chemical compound C1=CN=C2C(O)=CC=CC2=C1 MCJGNVYPOGVAJF-UHFFFAOYSA-N 0.000 claims description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 4
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 3
- 235000010290 biphenyl Nutrition 0.000 claims description 3
- 239000004305 biphenyl Substances 0.000 claims description 3
- 235000013877 carbamide Nutrition 0.000 claims description 3
- 239000000706 filtrate Substances 0.000 claims description 3
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 3
- 239000000741 silica gel Substances 0.000 claims description 3
- 229910002027 silica gel Inorganic materials 0.000 claims description 3
- 239000003814 drug Substances 0.000 claims 2
- 229940079593 drug Drugs 0.000 claims 2
- 238000011275 oncology therapy Methods 0.000 claims 2
- 238000004458 analytical method Methods 0.000 claims 1
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 57
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 46
- 238000005160 1H NMR spectroscopy Methods 0.000 description 23
- LUBJCRLGQSPQNN-UHFFFAOYSA-N 1-Phenylurea Chemical group NC(=O)NC1=CC=CC=C1 LUBJCRLGQSPQNN-UHFFFAOYSA-N 0.000 description 10
- 229910020323 ClF3 Inorganic materials 0.000 description 7
- CGCOVQSKNBEYNN-UHFFFAOYSA-N [4-(trifluoromethyl)phenyl]urea Chemical group NC(=O)NC1=CC=C(C(F)(F)F)C=C1 CGCOVQSKNBEYNN-UHFFFAOYSA-N 0.000 description 7
- LJSGLEVVMDHAGH-UHFFFAOYSA-N [4-chloro-3-(trifluoromethyl)phenyl]urea Chemical group NC(=O)NC1=CC=C(Cl)C(C(F)(F)F)=C1 LJSGLEVVMDHAGH-UHFFFAOYSA-N 0.000 description 7
- 239000000047 product Substances 0.000 description 5
- FLNMQGISZVYIIK-UHFFFAOYSA-N 1-ethylpyrazole Chemical class CCN1C=CC=N1 FLNMQGISZVYIIK-UHFFFAOYSA-N 0.000 description 4
- 206010028980 Neoplasm Diseases 0.000 description 4
- AYDQIZKZTQHYIY-UHFFFAOYSA-N OC(=O)C1(C)CC(C(O)=O)=CC=C1 Chemical compound OC(=O)C1(C)CC(C(O)=O)=CC=C1 AYDQIZKZTQHYIY-UHFFFAOYSA-N 0.000 description 4
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 4
- AKQAJYLKBCWJBV-UHFFFAOYSA-N 1-benzylpyrazole Chemical class C1=CC=NN1CC1=CC=CC=C1 AKQAJYLKBCWJBV-UHFFFAOYSA-N 0.000 description 3
- WITMXBRCQWOZPX-UHFFFAOYSA-N 1-phenylpyrazole Chemical class C1=CC=NN1C1=CC=CC=C1 WITMXBRCQWOZPX-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 101000984753 Homo sapiens Serine/threonine-protein kinase B-raf Proteins 0.000 description 3
- 102100027103 Serine/threonine-protein kinase B-raf Human genes 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 230000004907 flux Effects 0.000 description 3
- 238000003041 virtual screening Methods 0.000 description 3
- XJYIPDKSWROWBM-UHFFFAOYSA-N 1-(4-methylphenyl)pyrazole Chemical class C1=CC(C)=CC=C1N1N=CC=C1 XJYIPDKSWROWBM-UHFFFAOYSA-N 0.000 description 2
- 125000004207 3-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(OC([H])([H])[H])=C1[H] 0.000 description 2
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 2
- IATFOGDERDNVMS-UHFFFAOYSA-N 4-nitro-1-phenylpyrazole Chemical class C1=C([N+](=O)[O-])C=NN1C1=CC=CC=C1 IATFOGDERDNVMS-UHFFFAOYSA-N 0.000 description 2
- XORHNJQEWQGXCN-UHFFFAOYSA-N 4-nitro-1h-pyrazole Chemical class [O-][N+](=O)C=1C=NNC=1 XORHNJQEWQGXCN-UHFFFAOYSA-N 0.000 description 2
- 239000005711 Benzoic acid Substances 0.000 description 2
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 2
- 102000043136 MAP kinase family Human genes 0.000 description 2
- 108091054455 MAP kinase family Proteins 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 230000000118 anti-neoplastic effect Effects 0.000 description 2
- 229940054051 antipsychotic indole derivative Drugs 0.000 description 2
- 235000010233 benzoic acid Nutrition 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 150000002475 indoles Chemical class 0.000 description 2
- 238000012216 screening Methods 0.000 description 2
- 150000003457 sulfones Chemical class 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N urea group Chemical group NC(=O)N XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- XSIJAHHRQBFAAR-UHFFFAOYSA-N COc1cccc(-[n]2ncc(NC(c3cc(NC(Nc4ccc(C(F)(F)F)cc4)=O)ccc3)=O)c2)c1 Chemical compound COc1cccc(-[n]2ncc(NC(c3cc(NC(Nc4ccc(C(F)(F)F)cc4)=O)ccc3)=O)c2)c1 XSIJAHHRQBFAAR-UHFFFAOYSA-N 0.000 description 1
- VQHILXSRVFZXCC-UHFFFAOYSA-N C[n]1ncc(NC(c2cc(NC(Nc(cc3)ccc3Oc3ccccc3)=O)ccc2)=O)c1 Chemical compound C[n]1ncc(NC(c2cc(NC(Nc(cc3)ccc3Oc3ccccc3)=O)ccc2)=O)c1 VQHILXSRVFZXCC-UHFFFAOYSA-N 0.000 description 1
- 208000005623 Carcinogenesis Diseases 0.000 description 1
- LIQRJOQJRMRMKT-UHFFFAOYSA-N O=C(c1cccc(NC(Nc2ccccc2)=O)c1)Nc1c[n](-c2ccccc2)nc1 Chemical compound O=C(c1cccc(NC(Nc2ccccc2)=O)c1)Nc1c[n](-c2ccccc2)nc1 LIQRJOQJRMRMKT-UHFFFAOYSA-N 0.000 description 1
- 108091000080 Phosphotransferase Proteins 0.000 description 1
- 102000001253 Protein Kinase Human genes 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 229940034982 antineoplastic agent Drugs 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- YCOXTKKNXUZSKD-UHFFFAOYSA-N as-o-xylenol Natural products CC1=CC=C(O)C=C1C YCOXTKKNXUZSKD-UHFFFAOYSA-N 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- 230000036952 cancer formation Effects 0.000 description 1
- 231100000504 carcinogenesis Toxicity 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- SNHMUERNLJLMHN-UHFFFAOYSA-N iodobenzene Chemical compound IC1=CC=CC=C1 SNHMUERNLJLMHN-UHFFFAOYSA-N 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 102000006240 membrane receptors Human genes 0.000 description 1
- 108020004084 membrane receptors Proteins 0.000 description 1
- 239000003226 mitogen Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 238000003032 molecular docking Methods 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- 102000020233 phosphotransferase Human genes 0.000 description 1
- 108060006633 protein kinase Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000009834 vaporization Methods 0.000 description 1
- 230000008016 vaporization Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D231/38—Nitrogen atoms
- C07D231/40—Acylated on said nitrogen atom
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The invention discloses the diphenyl urea analog derivative of a class containing pyrazol framework and preparation method thereof, the structure of the diphenyl urea analog derivative containing pyrazol framework as shown in formula,Wherein, R1Selected from CH3、‑CH2CH3、R2Selected from H, CF3、‑Cl；R3Selected from H, CF3。
Description
Technical field
The invention belongs to medicinal chemistry art, more particularly to the diphenyl urea analog derivative containing pyrazol framework and its preparation side
Method.
Background technology
In recent years, with from cell, molecular level to the further understanding of Tumorigenesis, some produce in tumour and
The large biological molecule such as the key signal path and membrane receptor that are played a significant role in development, kinases is disclosed so that for this
A little efficient antineoplastics of tumor-specific molecule drone design low toxicity are possibly realized.Mitogen original activated protein kinase
(MAPK) signal transduction pathway is one of intracellular most important signal path, and BRAF is the key members in path MAPK, greatly
About 8% human tumor is found with V600E mutation BRAF (BRAFV600E), so as to cause downstream MEK-ERK signal paths to be held
Continuous abnormal activation, growth to tumour, breeds, attacks and shifts most important.Therefore, BRAFV600EIt is current antineoplastic
The popular target of research and development.
High flux virtual screening technology is the screening technique being commonly used.High flux virtual screening technology is by target protein
The computational screening technology that high-resolution crystal structure is carried out as template.First, using high flux virtual screening technology with
BRAFV600EAlbumen is that template filter comes out molecule of the skeleton.Then, using Discovery Studio softwares by molecule of the skeleton and
BRAFV600EAlbumen carries out molecular docking, and corresponding modification transformation is carried out to it, obtains best molecule of the skeleton.
The content of the invention
BRAF is used as it is an object of the invention to provide a classV600EThe diphenyl ureas containing pyrazol framework of target spot inhibitor
Derivative and preparation method thereof.
Technical scheme：Indole derivatives of one class containing pyrazol framework, its structure as shown in formula,
Wherein, R1Selected from-CH3、-CH2CH3、R2It is selected from
H、-CF3、-Cl；R3Selected from H ,-CF3。
A kind of method of the diphenyl urea analog derivative prepared containing pyrazol framework, the diphenyl ureas containing pyrazol framework
The structure of derivative as shown in formula,
Wherein, R1Selected from-CH3、-CH2CH3、R2It is selected from
H、-CF3、-Cl；R3Selected from H ,-CF3。
Preparation method comprises the following steps,
Pyrazoles (14g, 205.64mmol) is dissolved in the concentrated sulfuric acid (50mL), then by concentrated nitric acid by step 1. at 0 DEG C
(9.2M1,226.20mmol) is added dropwise, and temperature is heated slowly to 60 by whole reaction system by addition while stirring after terminating
℃.Whole reactant mixture agitating and heating is reacted into 1.5h.After question response terminates, reactant mixture is added to mixture of ice and water
In (600g).Stand after a period of time, reactant mixture has white solid precipitation, is then separated by filtration white solid, will
The white solid separated is dried after washing again, obtains the compound of a part of structural formula as indicated at a.By the filter after filtering
Liquid is extracted with ethyl acetate (100mL × 3), obtains organic phase.Sodium bicarbonate solution (100mL), water organic phase with 1%
(100mL) and saturated aqueous common salt (100mL) are rinsed successively.Finally, the ethyl acetate anhydrous sodium sulfate drying after will be treated
And vacuum decompression evaporation drying obtains the compound of another part structural formula as indicated at a.
Compound (7.14mmol), structural formula compound as shown in B of the step 2. by structural formula as indicated at a
It is sub- that (7.14mmol), 8-hydroxyquinoline (0.18g, 1.23mmol), potassium carbonate (1.8g, 13.02mmol) are dissolved in anhydrous dimethyl
In sulfone (9mL), the container where reactant mixture is then poured into argon gas, cuprous iodide (0.135g, 0.69mmol) is added.
Whole reaction system is heated to 130 DEG C, then agitating and heating reaction 20h.Suitable quantity of water is added to reaction by question response after terminating
In system, a large amount of solids can be produced.Solid is separated by filtration and dries and separating-purifying is carried out to it using silica gel column chromatography, is obtained
The compound of structural formula as shown at c.
The compound (4mmol) of structural formula as shown at c is dissolved in absolute ethyl alcohol (4mL) by step 3., is then added
80% hydrazine hydrate solution (2mL), 10% palladium carbon hydrogenation catalyst (0.08g).Then the temperature of reactant mixture is heated
To 80 DEG C, reaction system is heated while stirring and reacted 10 minutes.After question response terminates, reactant mixture is filtered, filter is collected
Liquid.Finally, filter vacuum is evaporated under reduced pressure and is dried to obtain the compound of structural formula as shown atd.
Gavaculine (2mmol) is dissolved in anhydrous tetrahydrofuran solution (15mL) by step 4., then by structure
Compound (2mmol) of the formula as shown in E is slowly added into.Whole reaction system is placed in stirring reaction 60 hours under normal temperature.Deng anti-
After should terminating, the white precipitate filtering of generation will be reacted, and with appropriate anhydrous methylene chloride or appropriate absolute ether
Washing, to obtain compound of the pure structural formula as shown in F.
Step 5. is by compound (0.25mmol) of the structural formula as shown in F, EDC (0.25mmol), HOBT (0.25mmol)
It is dissolved in dry DMF (5mL), reactant mixture is then positioned over stirring reaction 30 minutes under normal temperature., will after 30 minutes
Structural formula compound (0.25mmol) as shown atd, DMAP (0.25mmol), triethylamine (1mL) are added in reactant mixture,
Then reaction is stayed overnight while stirring at normal temperatures for whole reaction.After question response terminates, obtained reactant mixture saturated common salt
Water and ethyl acetate (100mL × 3) extraction, finally, obtain crude product, and utilize silica gel by organic phase vacuum decompression evaporation drying
Column chromatography carries out separating-purifying to it, obtains compound of the final structural formula as shown in G.
Wherein, R1Selected from-CH3、-CH2CH3、R2It is selected from
H、-CF3、-Cl；R3Selected from H ,-CF3。
Embodiment
In some specific embodiment, preparation process of the invention and the structural formula of associated products are as described below：
A kind of method for preparing the above-mentioned indole derivatives containing pyrazol framework, it comprises the following steps：
Pyrazoles (14g, 205.64mmol) is dissolved in the concentrated sulfuric acid (50mL), then by concentrated nitric acid by step 1. at 0 DEG C
(9.2Ml, 226.20mmol) is added dropwise, and temperature is heated slowly to 60 by whole reaction system by addition while stirring after terminating
℃.Whole reactant mixture agitating and heating is reacted into 1.5h.After question response terminates, reactant mixture is added to mixture of ice and water
In (600g).Stand after a period of time, reactant mixture has white solid precipitation, is then separated by filtration white solid, will
The white solid separated is dried after washing again, obtains the compound of a part of structural formula as indicated at a.By the filter after filtering
Liquid is extracted with ethyl acetate (100mL × 3), obtains organic phase.Sodium bicarbonate solution (100mL), water organic phase with 1%
(100mL) and saturated aqueous common salt (100mL) are rinsed successively.Finally, the ethyl acetate anhydrous sodium sulfate drying after will be treated
And vacuum decompression evaporation drying obtains the compound of another part structural formula as indicated at a.
Compound (7.14mmol), structural formula compound as shown in B of the step 2. by structural formula as indicated at a
It is sub- that (7.14mmol), 8-hydroxyquinoline (0.18g, 1.23mmol), potassium carbonate (1.8g, 13.02mmol) are dissolved in anhydrous dimethyl
In sulfone (9mL), the container where reactant mixture is then poured into argon gas, cuprous iodide (0.135g, 0.69mmol) is added.
Whole reaction system is heated to 130 DEG C, then agitating and heating reaction 20h.Suitable quantity of water is added to reaction by question response after terminating
In system, a large amount of solids can be produced.Solid is separated by filtration and dries and separating-purifying is carried out to it using silica gel column chromatography, is obtained
The compound of structural formula as shown at c.
The compound (4mmol) of structural formula as shown at c is dissolved in absolute ethyl alcohol (4mL) by step 3., is then added
80% hydrazine hydrate solution (2mL), 10% palladium carbon hydrogenation catalyst (0.08g).Then the temperature of reactant mixture is heated
To 80 DEG C, reaction system is heated while stirring and reacted 10 minutes.After question response terminates, reactant mixture is filtered, filter is collected
Liquid.Finally, filter vacuum is evaporated under reduced pressure and is dried to obtain the compound of structural formula as shown atd.
Gavaculine (2mmol) is dissolved in anhydrous tetrahydrofuran solution (15mL) by step 4., then by structure
Compound (2mmol) of the formula as shown in E is slowly added into.Whole reaction system is placed in stirring reaction 60 hours under normal temperature.Deng anti-
After should terminating, the white precipitate filtering of generation will be reacted, and with appropriate anhydrous methylene chloride or appropriate absolute ether
Washing, to obtain compound of the pure structural formula as shown in F.
Step 5. is by compound (0.25mmol) of the structural formula as shown in F, EDC (0.25mmol), HOBT (0.25mmol)
It is dissolved in dry DMF (5mL), reactant mixture is then positioned over stirring reaction 30 minutes under normal temperature., will after 30 minutes
Structural formula compound (0.25mmol) as shown atd, DMAP (0.25mmol), triethylamine (1mL) are added in reactant mixture,
Then reaction is stayed overnight while stirring at normal temperatures for whole reaction.After question response terminates, obtained reactant mixture saturated common salt
Water and ethyl acetate (100mL × 3) extraction, finally, obtain crude product, and utilize silica gel by organic phase vacuum decompression evaporation drying
Column chromatography carries out separating-purifying to it, obtains compound of the final structural formula as shown in G.
Embodiment one：The preparation of N- (1- phenyl -1H- pyrazoles -4- bases) -3- (3- phenyl urea groups) benzamide (5a)
At 0 DEG C, pyrazoles (14g, 205.64mmol) is dissolved in the concentrated sulfuric acid (50mL), then by concentrated nitric acid (9.2Ml,
226.20mmol) it is added dropwise, temperature is heated slowly to 60 DEG C by whole reaction system by addition while stirring after terminating.Will be whole
Individual reactant mixture agitating and heating reacts 1.5h.After question response terminates, reactant mixture is added to mixture of ice and water (600g)
In.Stand after a period of time, reactant mixture has white solid precipitation, is then separated by filtration white solid, will isolate
The white solid come is dried after washing again, obtains a part of product.By the filtrate after filtering with ethyl acetate (100mL × 3)
Extraction, obtains organic phase.Organic phase with 1% sodium bicarbonate solution (100mL), water (100mL) and saturated aqueous common salt
(100mL) is rinsed successively.Finally, ethyl acetate anhydrous sodium sulfate drying and vacuum decompression evaporation drying after will be treated
Obtain product 4- nitropyrazoles.By 4- nitropyrazoles (7.14mmol), iodobenzene (7.14mmol), 8-hydroxyquinoline (0.18g,
1.23mmol), potassium carbonate (1.8g, 13.02mmol) is dissolved in anhydrous dimethyl sulfoxide (9mL), then by reactant mixture institute
Container pour argon gas, add cuprous iodide (0.135g, 0.69mmol).Whole reaction system is heated to 130 DEG C, so
Agitating and heating reacts 20h afterwards.Suitable quantity of water is added in reaction system by question response after terminating, and can produce a large amount of solids.By solid
It is separated by filtration and dries and separating-purifying is carried out to it using silica gel column chromatography, obtains product 1- phenyl -4- nitropyrazoles.It will obtain
Product 1- phenyl -4- nitropyrazoles (4mmol) be dissolved in absolute ethyl alcohol (4mL), then add 80% hydrazine hydrate solution
(2mL), 10% palladium carbon hydrogenation catalyst (0.08g).Then the temperature of reactant mixture is heated to 80 DEG C, by reaction system
Heat while stirring reaction 10 minutes.After question response terminates, reactant mixture is filtered, filtrate is collected.Finally, by filter vacuum
Reduction vaporization is dried to obtain compound 1- phenyl -4- amino-pyrazols.Gavaculine (2mmol) is dissolved in anhydrous tetrahydrochysene furan
Mutter in solution (15mL), be then slowly added into compound phenyl isocyanate (2mmol).Whole reaction system is placed under normal temperature
Stirring reaction 60 hours.After terminating Deng reaction, the white precipitate filtering of generation will be reacted, and with appropriate anhydrous methylene chloride
Or appropriate absolute ether washing, to obtain pure compound 3- (3- phenyl urea groups) benzoic acid.By compound 3- (3- phenyl
Urea groups) benzoic acid (0.25mmol), EDC (0.25mmol), HOBT (0.25mmol) be dissolved in dry DMF (5mL), then will
Reactant mixture is positioned over stirring reaction 30 minutes under normal temperature.After 30 minutes, compound 1- phenyl -4- amino-pyrazols
(0.25mmol), DMAP (0.25mmol), triethylamine (1mL) are added in reactant mixture, then whole to react at normal temperatures
Reaction is stayed overnight while stirring.After question response terminates, obtained reactant mixture saturated aqueous common salt and ethyl acetate (100mL ×
3) extract, finally, organic phase vacuum decompression evaporation drying is obtained into crude product, and separation is carried out to it using silica gel column chromatography carry
It is pure, obtain final compound N-(1- phenyl -1H- pyrazoles -4- bases) -3- (3- phenyl urea groups) benzamide.White solid, production
Rate 84.1%, m.p.267.5~270.3 DEG C.1H NMR (600MHz, DMSO-d6)δ：10.64 (s, 1H, NH), 8.90 (s, 1H,
NH), 8.74 (s, 1H, NH), 8.71 (s, 1H, ArH), 8.06 (s, 1H, CH), 7.94 (s, 1H, ArH), 7.83 (d, J=
7.8Hz, 2H, ArH), 7.67 (d, J=8.1Hz, 1H, CH), 7.60 (d, J=7.8Hz, 1H, ArH), 7.49 (td, J=15.1,
14.3,7.8Hz, 5H, ArH), 7.30 (t, J=9.9Hz, 3H, ArH), 6.99 (t, J=7.3Hz, 1H, ArH) .MS EI+：
397.44(C23H19N5O2, [M]+).
Embodiment two：The preparation of N- (1- methyl isophthalic acid H- pyrazoles -4- bases) -3- (3- phenyl urea groups) benzamide (5b)
Preparation method reference implementation example one.White solid, yield 84.6%, 300 DEG C of m.p. ＞.1H NMR (600MHz,
DMSO-d6)δ：10.41 (s, 1H, NH), 8.87 (s, 1H, NH), 8.72 (s, 1H, NH), 8.04 (s, 1H, ArH), 7.99 (s,
1H, CH), 7.65 (d, J=9.4Hz, 1H, ArH), 7.58 (s, 1H, ArH), 7.54 (d, J=7.7Hz, 1H, ArH), 7.48 (d,
J=7.7Hz, 2H, ArH), 7.42 (t, J=7.9Hz, 1H, ArH), 7.30 (t, J=7.9Hz, 2H, ArH), 6.99 (t, J=
7.3Hz, 1H, CH), 3.83 (s, 3H, CH3).MS EI+：335.37(C18H17N5O2, [M]+) and
Embodiment three：The preparation of N- (1- ethyl -1H- pyrazoles -4- bases) -3- (3- phenyl urea groups) benzamide (5c)
Preparation method reference implementation example one.White solid, yield 81.7%, m.p.254.9~256.3 DEG C.1H NMR
(600MHz, DMSO-d6)δ：10.41 (s, 1H, NH), 8.87 (s, 1H, NH), 8.72 (s, 1H, NH), 8.07 (s, 1H, ArH),
7.99 (s, 1H, CH), 7.66 (d, J=6.9Hz, 1H, ArH), 7.60 (s, 1H, ArH), 7.55 (d, J=7.7Hz, 1H, ArH),
7.49 (d, J=7.9Hz, 2H, ArH), 7.43 (t, J=7.9Hz, 1H, CH), 7.30 (t, J=7.9Hz, 2H, ArH), 7.01-
6.97 (m, 1H, ArH), 4.13 (q, J=7.3Hz, 2H, CH2), 1.37 (t, J=7.3Hz, 3H, CH3).MS EI+：349.39
(C19H19N5O2, [M]+).
Example IV：The preparation of N- (1- benzyl -1H- pyrazoles -4- bases) -3- (3- phenyl urea groups) benzamide (5d)
Preparation method reference implementation example one.White solid, yield 85.4%, m.p.254.6~256.7 DEG C.1H NMR
(600MHz, DMSO-d6)δ：10.45 (s, 1H, NH), 8.90 (s, 1H, NH), 8.75 (s, 1H, NH), 8.16 (s, 1H, ArH),
7.98 (s, 1H, CH), 7.65 (d, J=15.3Hz, 2H, ArH), 7.54 (d, J=7.8Hz, 1H, ArH), 7.48 (d, J=
7.7Hz, 2H, ArH), 7.42 (t, J=7.9Hz, 1H, ArH), 7.36 (t, J=7.4Hz, 2H, ArH), 7.30 (t, J=
7.9Hz, 3H, ArH), 7.26 (d, J=7.2Hz, 2H, ArH), 6.99 (t, J=7.3Hz, 1H, CH), 5.33 (s, 2H, CH2)
.MS EI+：411.47(C24H21N5O2, [M]+).
Embodiment five：The system of 3- (3- phenyl urea groups)-N- (1- (p-methylphenyl) -1H- pyrazoles -4- bases) benzamide (5e)
It is standby
Preparation method reference implementation example one.White solid, yield 86.3%, m.p.273.8~276.6 DEG C.1H NMR
(600MHz, DMSO-d6)δ：10.63 (s, 1H, NH), 8.90 (s, 1H, NH), 8.74 (s, 1H, NH), 8.66 (s, 1H, ArH),
8.05 (s, 1H, CH), 7.90 (s, 1H, ArH), 7.69 (dd, J=14.9,8.2Hz, 3H, ArH), 7.59 (d, J=7.8Hz,
1H, CH), 7.50-7.44 (m, 3H, ArH), 7.32-7.29 (m, 4H, ArH), 6.99 (t, J=7.3Hz, 1H, ArH), 2.34
(s, 3H, CH3).MS EI+：411.47(C24H21N5O2, [M]+).
Embodiment six：N- (1- (4- methoxyphenyls) -1H- pyrazoles -4- bases) -3- (3- phenyl urea groups) benzamide (5f)
Preparation
Preparation method reference implementation example one.White solid, yield 80.8%, m.p.277.8~280.6 DEG C.1H NMR
(600MHz, DMSO-d6)δ：10.61 (s, 1H, NH), 8.90 (s, 1H, NH), 8.74 (s, 1H, NH), 8.60 (s, 1H, ArH),
8.05 (s, 1H, CH), 7.88 (s, 1H, ArH), 7.73 (d, J=9.0Hz, 2H, ArH), 7.67 (d, J=9.4Hz, 1H, CH),
7.59 (d, J=7.9Hz, 1H, ArH), 7.49 (d, J=7.6Hz, 2H, ArH), 7.45 (t, J=7.9Hz, 1H, ArH), 7.32-
7.28 (m, 2H, ArH), 7.06 (d, J=9.1Hz, 2H, ArH), 6.99 (t, J=7.3Hz, 1H, ArH), 3.80 (s, 3H,
CH3).MS EI+：427.46(C24H21N5O3, [M]+).
Embodiment seven：N- (1- (3- methoxyphenyls) -1H- pyrazoles -4- bases) -3- (3- phenyl urea groups) benzamide (5g)
Preparation
Preparation method reference implementation example one.White solid, yield 81.5%, m.p.220.6~223.1 DEG C.1H NMR
(600MHz, DMSO-d6)δ：10.63 (s, 1H, NH), 8.90 (s, 1H, NH), 8.74 (s, 1H, NH), 8.72 (s, 1H, ArH),
8.06 (s, 1H, CH), 7.93 (s, 1H, ArH), 7.68 (d, J=8.0Hz, 1H, ArH), 7.59 (d, J=7.8Hz, 1H, CH),
7.49 (d, J=7.8Hz, 2H, ArH), 7.46 (t, J=7.9Hz, 1H, ArH), 7.40 (t, J=5.3Hz, 3H, ArH), 7.32-
7.29 (m, 2H, ArH), 6.99 (t, J=7.3Hz, 1H, ArH), 6.88 (dt, J=6.1,2.7Hz, 1H, ArH), 3.85 (s,
3H, CH3).MS EI+：427.46(C24H21N5O3, [M]+).
Embodiment eight：N- (1- methyl isophthalic acid H- pyrazoles -4- bases) -3- (3- (4- (trifluoromethyl) phenyl) urea groups) benzamide
The preparation of (5h)
Preparation method reference implementation example one.Gray solid, yield 82.6%, m.p.271.3~273.5 DEG C.1H NMR
(600MHz, DMSO-d6)δ：10.42 (s, 1H, NH), 9.16 (s, 1H, NH), 9.02 (s, 1H, NH), 8.04 (s, 1H, ArH),
8.01 (s, 1H, CH), 7.70 (d, J=8.7Hz, 2H, ArH), 7.68-7.64 (m, 3H, ArH), 7.58 (d, J=8.7Hz, 2H,
ArH), 7.44 (t, J=7.9Hz, 1H, CH), 3.83 (s, 3H, CH3).MS EI+：403.37(C19H16F3N5O2, [M]+).
Embodiment nine：N- (1- ethyl -1H- pyrazoles -4- bases) -3- (3- (4- (trifluoromethyl) phenyl) urea groups) benzamide
The preparation of (5i)
Preparation method reference implementation example one.White solid, yield 82.3%, m.p.238.2~240.9 DEG C.1H NMR
(600MHz, DMSO-d6)δ：10.42 (s, 1H, NH), 9.16 (s, 1H, NH), 9.01 (s, 1H, NH), 8.07 (s, 1H, ArH),
8.01 (s, 1H, CH), 7.71-7.64 (m, 5H, ArH), 7.58 (d, J=16.0Hz, 2H, ArH), 7.45 (t, J=7.9Hz,
1H, ArH), 4.13 (q, J=7.3Hz, 2H, CH2), 1.37 (t, J=7.3Hz, 3H, CH3).MS EI+：417.39
(C20H18F3N5O2, [M]+).
Embodiment ten：N- (1- benzyl -1H- pyrazoles -4- bases) -3- (3- (4- (trifluoromethyl) phenyl) urea groups) benzamide
The preparation of (5j)
Preparation method reference implementation example one.Yellow solid, yield 81.5%, m.p.258.8~261.3 DEG C.1H NMR
(600MHz, DMSO-d6)δ：10.46 (s, 1H, NH), 9.17 (s, 1H, NH), 9.02 (s, 1H, NH), 8.16 (s, 1H, ArH),
8.00 (s, 1H, CH), 7.70-7.64 (m, 6H, ArH), 7.57 (d, J=7.7Hz, 1H, CH), 7.44 (t, J=7.9Hz, 1H,
ArH), 7.36 (t, J=7.4Hz, 2H, ArH), 7.30 (t, J=7.3Hz, 1H, ArH), 7.26 (d, J=7.4Hz, 2H, ArH),
5.33 (s, 2H, CH2).MS EI+：479.46(C25H20F3N5O2, [M]+).
Embodiment 11：N- (1- phenyl -1H- pyrazoles -4- bases) -3- (3- (4- (trifluoromethyl) phenyl) urea groups) benzoyl
The preparation of amine (5k)
Preparation method reference implementation example one.White solid, yield 80.1%, m.p.276.8~279.6 DEG C.1H NMR
(400MHz, DMSO-d6)δ：10.65 (s, 1H, NH), 9.18 (s, 1H, NH), 9.04 (s, 1H, NH), 8.71 (s, 1H, ArH),
8.08 (s, 1H, CH), 7.94 (s, 1H, ArH), 7.83 (d, J=8.3Hz, 2H, ArH), 7.67 (dt, J=19.9,9.6Hz,
6H, ArH), 7.50 (dt, J=15.2,7.8Hz, 3H, ArH), 7.31 (t, J=7.3Hz, 1H, ArH) .MS EI+：465.44
(C24H18F3N5O2, [M]+).
Embodiment 12：N- (1- (p-methylphenyl) -1H- pyrazoles -4- bases) -3- (3- (4- (trifluoromethyl) phenyl) urea groups)
The preparation of benzamide (5l)
Preparation method reference implementation example one.White solid, yield 80.5%, m.p.270.7~273.0 DEG C.1H NMR
(400MHz, DMSO-d6)δ：10.63 (s, 1H, NH), 9.17 (s, 1H, NH), 9.04 (s, 1H, NH), 8.66 (s, 1H, ArH),
8.07 (s, 1H, CH), 7.91 (s, 1H, CH), 7.67 (dt, J=19.6,9.3Hz, 8H, ArH), 7.48 (t, J=7.9Hz, 1H,
ArH), 7.30 (d, J=8.4Hz, 2H, ArH), 2.34 (s, 3H, CH3).MS EI+：479.46(C25H20F3N5O2, [M]+).
Embodiment 13：N- (1- (4- methoxyphenyls) -1H- pyrazoles -4- bases) -3- (3- (4- (trifluoromethyl) phenyl)
Urea groups) benzamide (5m) preparation
Preparation method reference implementation example one.Yellow solid, yield 83.4%, m.p.282.0~284.0 DEG C.1H NMR
(600MHz, DMSO-d6)δ：10.62 (s, 1H, NH), 9.18 (s, 1H, NH), 9.04 (s, 1H, NH), 8.60 (s, 1H, ArH),
8.07 (s, 1H, CH), 7.88 (s, 1H, ArH), 7.74 (s, 1H, ArH), 7.73 (s, 1H, CH), 7.70 (d, J=8.7Hz, 2H,
ArH), 7.66 (t, J=8.0Hz, 3H, ArH), 7.62 (d, J=7.8Hz, 1H, ArH), 7.47 (t, J=7.9Hz, 1H, ArH),
7.06 (d, J=9.0Hz, 2H, ArH), 3.81 (s, 3H, CH3).MS EI+：495.46(C25H20F3N5O3, [M]+).
Embodiment 14：N- (1- (3- methoxyphenyls) -1H- pyrazoles -4- bases) -3- (3- (4- (trifluoromethyl) phenyl)
Urea groups) benzamide (5n) preparation
Preparation method reference implementation example one.White solid, yield 82.2%, m.p.223.0~225.7 DEG C.1H NMR
(600MHz, DMSO-d6)δ：10.65 (s, 1H, NH), 9.18 (s, 1H, NH), 9.04 (s, 1H, NH), 8.73 (s, 1H, ArH),
8.09 (s, 1H, CH), 7.94 (s, 1H, ArH), 7.70 (t, J=9.3Hz, 3H, ArH), 7.66 (d, J=8.8Hz, 2H, ArH),
7.63 (d, J=8.1Hz, 1H, CH), 7.48 (t, J=7.9Hz, 1H, ArH), 7.42-7.38 (m, 3H, ArH), 6.91-6.84
(m, 1H, ArH), 3.85 (s, 3H, CH3).MS EI+：495.46(C25H20F3N5O3, [M]+) and
Embodiment 15：N- (1- methyl isophthalic acid H- pyrazoles -4- bases) -3- (3- (4- Phenoxyphenyls) urea groups) benzamide
The preparation of (5o)
Preparation method reference implementation example one.Yellow solid, yield 86.5%, m.p.243.8~247.6 DEG C.1H NMR
(600MHz, DMSO-d6)δ：10.41 (s, 1H, NH), 8.87 (s, 1H, NH), 8.75 (s, 1H, NH), 8.03 (s, 1H, ArH),
7.98 (s, 1H, CH), 7.65 (d, J=8.1Hz, 1H, ArH), 7.58 (s, 1H, ArH), 7.54 (d, J=7.8Hz, 1H, ArH),
7.50 (d, J=8.9Hz, 2H, ArH), 7.42 (t, J=7.9Hz, 1H, ArH), 7.39-7.35 (m, 2H, ArH), 7.10 (t, J
=7.4Hz, 1H, CH), 6.98 (dd, J=18.6,8.3Hz, 4H, ArH), 3.83 (s, 3H, CH3).MS EI+：427.46
(C24H21N5O3, [M]+) and
Embodiment 16：N- (1- ethyl -1H- pyrazoles -4- bases) -3- (3- (4- Phenoxyphenyls) urea groups) benzamide
The preparation of (5p)
Preparation method reference implementation example one.Yellow solid, yield 84.4%, m.p.252.9~255.1 DEG C.1H NMR
(600MHz, DMSO-d6)δ：10.40 (s, 1H, NH), 8.90 (s, 1H, NH), 8.78 (s, 1H, NH), 8.06 (s, 1H, ArH),
7.98 (s, 1H, CH), 7.66 (d, J=8.0Hz, 1H, ArH), 7.59 (s, 1H, ArH), 7.53 (d, J=7.8Hz, 1H, ArH),
7.50 (d, J=8.9Hz, 2H, ArH), 7.42 (t, J=7.9Hz, 1H, ArH), 7.39-7.36 (m, 2H, ArH), 7.10 (t, J
=7.4Hz, 1H, CH), 6.98 (dd, J=18.2,8.3Hz, 4H, ArH), 4.12 (q, J=7.3Hz, 2H, CH2), 1.36 (t, J
=7.3Hz, 3H, CH3).MS EI+：441.49(C25H23N5O3, [M]+) and
Embodiment 17：3- (3- (4- chloro- 3- (trifluoromethyl) phenyl) urea groups)-N- (1- methyl isophthalic acid H- pyrazoles -4- bases)
The preparation of benzamide (5q)
Preparation method reference implementation example one.White solid, yield 81.1%, m.p.251.5~254.3 DEG C.1H NMR
(600MHz, DMSO-d6)δ：10.41 (s, 1H, NH), 9.22 (s, 1H, NH), 9.06 (s, 1H, NH), 8.14 (d, J=2.5Hz,
1H, ArH), 8.03 (s, 1H, CH), 8.01 (s, 1H, ArH), 7.68-7.64 (m, 2H, ArH), 7.63 (d, J=8.8Hz, 1H,
ArH), 7.57 (d, J=4.3Hz, 2H, ArH), 7.44 (t, J=7.9Hz, 1H, CH), 3.83 (s, 3H, CH3).MS EI+：
437.81(C19H15ClF3N5O2, [M]+) and
Embodiment 18：3- (3- (4- chloro- 3- (trifluoromethyl) phenyl) urea groups)-N- (1- ethyl -1H- pyrazoles -4- bases)
The preparation of benzamide (5r)
Preparation method reference implementation example one.White solid, yield 82.9%, m.p.236.5~239 DEG C.1H NMR
(600MHz, DMSO-d6)δ：10.41 (s, 1H, NH), 9.22 (s, 1H, NH), 9.06 (s, 1H, NH), 8.14 (s, 1H, ArH),
8.06 (s, 1H, CH), 8.01 (s, 1H, ArH), 7.64 (dd, J=17.4,7.9Hz, 3H, ArH), 7.61-7.56 (m, 2H,
ArH), 7.44 (t, J=7.9Hz, 1H, CH), 4.12 (q, J=7.2Hz, 2H, CH2), 1.36 (t, J=7.2Hz, 3H, CH3).MS
EI+：451.83(C20H17ClF3N5O2, [M]+) and
Embodiment 19：(1- benzyl -1H- pyrazoles -4- bases) -3- (3- (4- chloro- 3- (trifluoromethyl) phenyl) urea groups) benzene
The preparation of formamide (5s)
Preparation method reference implementation example one.White solid, yield 85.5%, m.p.218.4~221.2 DEG C.1H NMR
(600MHz, DMSO-d6)δ：10.45 (s, 1H, NH), 9.22 (s, 1H, NH), 9.05 (s, 1H, NH), 8.15 (s, 1H, ArH),
8.14 (d, J=2.4Hz, 1H, CH), 8.00 (s, 1H, ArH), 7.66 (q, J=4.8,3.3Hz, 2H, ArH), 7.63 (d, J=
10.4Hz, 2H, ArH), 7.57 (d, J=7.8Hz, 1H, ArH), 7.44 (t, J=7.9Hz, 1H, ArH), 7.36 (t, J=
7.4Hz, 2H, ArH), 7.30 (t, J=7.3Hz, 1H, CH), 7.26 (d, J=7.1Hz, 2H, ArH), 5.33 (s, 2H, CH2)
.MS EI+：513.91(C25H19ClF3N5O2, [M]+) and
Embodiment 20：3- (3- (4- chloro- 3- (trifluoromethyl) phenyl) urea groups)-N- (1- phenyl -1H- pyrazoles -4- bases)
The preparation of benzamide (5t)
Preparation method reference implementation example one.White solid, yield 82.8%, m.p.241.8~241.6 DEG C.1H NMR
(600MHz, DMSO-d6)δ：10.65 (s, 1H, NH), 9.24 (s, 1H, NH), 9.09 (s, 1H, NH), 8.71 (s, 1H, ArH),
8.15 (d, J=2.5Hz, 1H, CH), 8.09 (s, 1H, ArH), 7.94 (s, 1H, ArH), 7.83 (d, J=7.6Hz, 2H, ArH),
7.70-7.66 (m, 2H, ArH), 7.63 (d, J=8.4Hz, 2H, ArH), 7.49 (dt, J=19.2,7.7Hz, 3H, ArH),
7.31 (t, J=7.4Hz, 1H, ArH) .MS EI+：499.88(C24H17ClF3N5O2, [M]+) and
Embodiment 21：3- (3- (4- chloro- 3- (trifluoromethyl) phenyl) urea groups)-N- (1- (p-methylphenyl) -1H- pyrroles
Azoles -4- bases) benzamide (5u) preparation
Preparation method reference implementation example one.White solid, yield 80.3%, m.p.287.7~290.2 DEG C.1H NMR
(600MHz, DMSO-d6)δ：10.63 (s, 1H, NH), 9.24 (s, 1H, NH), 9.08 (s, 1H, NH), 8.65 (s, 1H, ArH),
8.16 (s, 1H, CH), 8.08 (s, 1H, ArH), 7.90 (s, 1H, ArH), 7.72-7.66 (m, 4H, ArH), 7.63 (d, J=
8.9Hz, 2H, ArH), 7.47 (t, J=7.9Hz, 1H, ArH), 7.30 (d, J=8.1Hz, 2H, ArH), 2.34 (s, 3H, CH3)
.MS EI+：513.91(C25H19ClF3N5O2, [M]+) and
Embodiment 22：3- (3- (4- chloro- 3- (trifluoromethyl) phenyl) urea groups)-N- (1- (4- methoxyphenyls)-
1H- pyrazoles -4- bases) benzamide (5v) preparation
Preparation method reference implementation example one.White solid, yield 81.7%, m.p.292.2~294.7 DEG C.1H NMR
(600MHz, DMSO-d6)δ：10.61 (s, 1H, NH), 9.24 (s, 1H, NH), 9.08 (s, 1H, NH), 8.60 (s, 1H, ArH),
8.15 (d, J=2.5Hz, 1H, CH), 8.08 (s, 1H, ArH), 7.88 (s, 1H, ArH), 7.73 (d, J=9.0Hz, 2H, ArH),
7.68 (d, J=8.5Hz, 2H, ArH), 7.63 (d, J=8.6Hz, 2H, ArH), 7.47 (t, J=7.9Hz, 1H, CH), 7.06
(d, J=9.1Hz, 2H, ArH), 3.80 (s, 3H, CH3).MS EI+：529.90(C25H19ClF3N5O3, [M]+) and
Embodiment 23：3- (3- (4- chloro- 3- (trifluoromethyl) phenyl) urea groups)-N- (1- (3- methoxyphenyls)-
1H- pyrazoles -4- bases) benzamide (5w) preparation
Preparation method reference implementation example one.White solid, yield 88.5%, m.p.236.6~239.3 DEG C.1H NMR
(600MHz, DMSO-d6)δ：10.64 (s, 1H, NH), 9.24 (s, 1H, NH), 9.09 (s, 1H, NH), 8.71 (s, 1H, ArH),
8.15 (d, J=2.5Hz, 1H, CH), 8.08 (s, 1H, ArH), 7.92 (s, 1H, ArH), 7.69-7.66 (m, 2H, ArH), 7.63
(d, J=9.3Hz, 2H, ArH), 7.47 (t, J=7.9Hz, 1H, CH), 7.40 (t, J=6.4Hz, 3H, ArH), 6.89-6.87
(m, 1H, ArH), 3.85 (s, 3H, CH3).MS EI+：529.90(C25H19ClF3N5O3, [M]+) and
The preferred embodiment of the present invention described in detail above, still, the present invention are not limited in above-mentioned embodiment
Detail, in the range of the technology design of the present invention, a variety of equivalents can be carried out to technical scheme, this
A little equivalents belong to protection scope of the present invention.It is further to note that described in above-mentioned embodiment
Each particular technique feature, in the case of reconcilable, can be combined by any suitable means.In order to avoid not
Necessary repetition, the present invention no longer separately illustrates to various possible combinations.In addition, a variety of implementations of the present invention
It can also be combined between mode, as long as it is without prejudice to the thought of the present invention, it is public that it should equally be considered as institute of the invention
The content opened.
Claims (4)
1. diphenyl urea analog derivative of the class containing pyrazol framework, its structure as shown in formula,
Wherein, R1Selected from-CH3、-CH2CH3、R2Selected from H ,-
CF3、-Cl；R3Selected from H ,-CF3。
2. a kind of method of the diphenyl urea analog derivative prepared containing pyrazol framework, the diphenyl ureas containing pyrazol framework spreads out
Biological structure as shown in formula,
Wherein, R1Selected from-CH3、-CH2CH3、R2Selected from H ,-
CF3、-Cl；R3Selected from H ,-CF3。
Preparation method comprises the following steps,
Pyrazoles (14g, 205.64mmol) is dissolved in the concentrated sulfuric acid (50mL), then by concentrated nitric acid by step 1. at 0 DEG C
(9.2Ml, 226.20mmol) is added dropwise, and temperature is heated slowly to 60 by whole reaction system by addition while stirring after terminating
℃.Whole reactant mixture agitating and heating is reacted into 1.5h.After question response terminates, reactant mixture is added to mixture of ice and water
In (600g).Stand after a period of time, reactant mixture has white solid precipitation, is then separated by filtration white solid, will
The white solid separated is dried after washing again, obtains the compound of a part of structural formula as indicated at a.By the filter after filtering
Liquid is extracted with ethyl acetate (100mL × 3), obtains organic phase.Sodium bicarbonate solution (100mL), water organic phase with 1%
(100mL) and saturated aqueous common salt (100mL) are rinsed successively.Finally, the ethyl acetate anhydrous sodium sulfate drying after will be treated
And vacuum decompression evaporation drying obtains the compound of another part structural formula as indicated at a.
Step 2. by compound (7.14mmol) of the structural formula compound (7.14mmol), structural formula as indicated at a as shown in B,
8-hydroxyquinoline (0.18g, 1.23mmol), potassium carbonate (1.8g, 13.02mmol) are dissolved in anhydrous dimethyl sulfoxide (9mL), so
The container where reactant mixture is poured into argon gas afterwards, cuprous iodide (0.135g, 0.69mmol) is added.By whole reactant
System is heated to 130 DEG C, then agitating and heating reaction 20h.Suitable quantity of water is added in reaction system by question response after terminating, and can be produced
A large amount of solids.Solid is separated by filtration and dries and separating-purifying is carried out to it using silica gel column chromatography, structural formula is obtained as shown at c
Compound.
The compound (4mmol) of structural formula as shown at c is dissolved in absolute ethyl alcohol (4mL) by step 3., then adds 80%
Hydrazine hydrate solution (2mL), 10% palladium carbon hydrogenation catalyst (0.08g).Then the temperature of reactant mixture is heated to 80 DEG C,
Reaction system is heated while stirring and reacted 10 minutes.After question response terminates, reactant mixture is filtered, filtrate is collected.Finally,
Filter vacuum is evaporated under reduced pressure and is dried to obtain the compound of structural formula as shown atd.
Gavaculine (2mmol) is dissolved in anhydrous tetrahydrofuran solution (15mL) by step 4., then by structural formula such as E
Shown compound (2mmol) is slowly added into.Whole reaction system is placed in stirring reaction 60 hours under normal temperature.Terminate Deng reaction
Afterwards, the white precipitate for reacting generation is filtered, and washed with appropriate anhydrous methylene chloride or appropriate absolute ether, with
Obtain compound of the pure structural formula as shown in F.
Step 5. dissolves compound (0.25mmol) of the structural formula as shown in F, EDC (0.25mmol), HOBT (0.25mmol)
In dry DMF (5mL), reactant mixture is then positioned over stirring reaction 30 minutes under normal temperature.After 30 minutes, by structure
Formula compound (0.25mmol) as shown atd, DMAP (0.25mmol), triethylamine (1mL) are added in reactant mixture, then
Reaction is stayed overnight while stirring at normal temperatures for whole reaction.After question response terminates, obtained reactant mixture saturated aqueous common salt and
Ethyl acetate (100mL × 3) is extracted, and finally, organic phase vacuum decompression evaporation drying is obtained into crude product, and utilize silica gel column layer
Analysis carries out separating-purifying to it, obtains compound of the final structural formula as shown in G.
Wherein, R1Selected from-CH3、-CH2CH3、 R2Selected from H ,-CF3、-Cl；R3Selected from H ,-CF3。
3. application of the diphenyl urea analog derivative in cancer therapy drug is prepared containing pyrazol framework, it is characterised in that its structure is such as
Shown in formula
Wherein, R1Selected from-CH3、-CH2CH3、R2Selected from H ,-CF3、-Cl；R3Selected from H ,-CF3。
4. a kind of cancer therapy drug, it is characterised in that including compound of the structure as shown in formula and medically acceptable carrier,
Wherein, R1Selected from-CH3、-CH2CH3、R2Selected from H ,-CF3、-Cl；R3Selected from H ,-CF3。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710511604.6A CN107118157A (en) | 2017-06-23 | 2017-06-23 | The design and synthesis of diphenyl urea analog derivative antitumoral compounds of one class containing pyrazol framework |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710511604.6A CN107118157A (en) | 2017-06-23 | 2017-06-23 | The design and synthesis of diphenyl urea analog derivative antitumoral compounds of one class containing pyrazol framework |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN107118157A true CN107118157A (en) | 2017-09-01 |
Family
ID=59718831
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201710511604.6A Pending CN107118157A (en) | 2017-06-23 | 2017-06-23 | The design and synthesis of diphenyl urea analog derivative antitumoral compounds of one class containing pyrazol framework |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN107118157A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111848506A (en) * | 2020-08-21 | 2020-10-30 | 中国药科大学 | Biphenyl urea compound and pharmaceutical composition, preparation method and application thereof |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103313968A (en) * | 2010-11-15 | 2013-09-18 | Abbvie公司 | Nampt and rock inhibitors |
-
2017
- 2017-06-23 CN CN201710511604.6A patent/CN107118157A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103313968A (en) * | 2010-11-15 | 2013-09-18 | Abbvie公司 | Nampt and rock inhibitors |
Non-Patent Citations (2)
| Title |
|---|
| DURINI,MARCO,ET AL.,: ""SupraBox: chiral supramolecular oxazoline ligands"", 《EUROPEAN JOURNAL OF ORGANIC CHEMISTRY》 * |
| WANG,PENG-FEI,ET AL.,: ""Identification of novel B-RafV600E inhibitors employing FBDD strategy"", 《BIOCHEMICAL PHARMACOLOGY》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111848506A (en) * | 2020-08-21 | 2020-10-30 | 中国药科大学 | Biphenyl urea compound and pharmaceutical composition, preparation method and application thereof |
| CN111848506B (en) * | 2020-08-21 | 2023-01-31 | 中国药科大学 | Biphenyl urea compound and pharmaceutical composition, preparation method and application thereof |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Zhang et al. | Organocatalytic asymmetric Henry reaction of isatins: Highly enantioselective synthesis of 3-hydroxy-2-oxindoles | |
| CN104945299B (en) | A kind of high-efficiency synthesis method of vildagliptin | |
| CN102746210A (en) | Synthesis method for key intermediate of silodosin | |
| CN113336689B (en) | Synthesis method and anticancer activity of 3- (alpha-fluorovinyl/carbonyl) indole compound | |
| CN107235958A (en) | A kind of synthetic method for preparing PARP inhibitor Niraparib | |
| Yokosaka et al. | Synthesis of fused-tricyclic indole derivatives through an acid-promoted skeletal rearrangement | |
| CN106632244A (en) | A novel synthetic method for preparing an anticancer medicine Niraparib | |
| CN107118157A (en) | The design and synthesis of diphenyl urea analog derivative antitumoral compounds of one class containing pyrazol framework | |
| CN109694330A (en) | A kind of preparation method of acid | |
| CN105461688B (en) | Benzimidazole compound K synthetic method | |
| WO2015123998A1 (en) | Method for synthesizing vildagliptin | |
| CN107417592A (en) | A kind of oxoaGetamide derivative of 1H indoles 2 and preparation method and application | |
| CN113912609B (en) | Preparation method of natural alkaloid tryptanthrin and derivatives thereof | |
| CN107880029A (en) | Design, synthesis and the application of a kind of indole derivatives antitumoral compounds containing pyrazol framework | |
| JP2009035531A (en) | Method for producing hydrazide compound and 1-substituted-1,2-dihydroindazol-3-one derivative, hydrazide compound and 1-substituted-1,2-dihydroindazol-3-one derivative | |
| CN106986860A (en) | Design, the synthesis of the pyrazoles anti-tumor compounds of one class amide bond | |
| CN115960003A (en) | Synthesis method of meta-hydroxylamine bitartrate | |
| Ishimoto et al. | Convergent and streamlined synthesis of 6-etherified imidazo [1, 2-b] pyridazine-2-amine derivatives possessing VEGFR-2 kinase inhibitory activity | |
| WO2012062109A1 (en) | Methods for preparation of pharmaceutical intermediates of aliskiren | |
| CN113135852A (en) | Preparation method of 4-aminoquinoline compound | |
| CN103772282B (en) | A kind of preparation method of the 3-tertiary butyl-1H-pyrazoles-4-formaldehyde | |
| CN107098861A (en) | Design, the synthesis of benzamide anti-tumor compounds of one class containing pyrazole ring | |
| CN105017269B (en) | A kind of different tetronic acid derivatives of chiral spiro and its preparation | |
| CN108530445A (en) | A kind of synthetic method of 3- cyanoimidazoles simultaneously [1,5-a] quinoline compound | |
| CN110256407A (en) | One kind -3- hydroxyl oxoindole derivative of substitution containing pyrazolone and preparation method |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20170901 |
|
| WD01 | Invention patent application deemed withdrawn after publication |